WO1997042944A1

WO1997042944A1 - Topical composition

Info

Publication number: WO1997042944A1
Application number: PCT/EP1997/002417
Authority: WO
Inventors: Beat Schmid; Werner Tschollar
Original assignee: Novartis Consumer Health S.A.
Priority date: 1996-05-13
Filing date: 1997-05-12
Publication date: 1997-11-20
Also published as: AU2953497A; ZA974126B

Abstract

The invention relates to the topical use of non-steroidal antiinflammatory drugs in combination with menthyl lactate (for the manufacture of a topical medicament) for the treatment of painful conditions, inflammatory conditions or rheumatic diseases, as well as to novel topical pharmaceutical compositions comprising a mixture of a non-steroidal antiinflammatory drug with menthyl lactate.

Description

Topical Composition

The invention relates to the topical (= external) treatment of painful conditions, inflammatory conditions and rheumatic diseases with non-steroidal antiinflammatory drugs (NSAIDs) as well as to novel topical pharmaceutical compositions comprising topically applicable NSAIDs.

The topical application of NSAIDs for the treatment of painful conditions, inflammatory conditions and rheumatic diseases is known in the art.

It has now surprisingly been found that by topical application of an NSAID together with menthyl lactate the analgesic, antiinflammatory and antirheumatic efficacy of the combination is enhanced.

Therefore, the invention relates to the topical use of at least one topically applicable non¬ steroidal antiinflammatory drug in combination with menthyl lactate (for the manufacture of a topical medicament) for the treatment of painful conditions, inflammatory conditions or rheumatic diseases.

A topically applicable non-steroidal antiinflammatory drug is, for example, salicylic acid or a derivative thereof, e.g. acetaminosalol, aspirin, benorylate, bromosaligenin, calcium acetylsalicylate, diflunisal, etersalate, fendosal, gentisic acid, glycol salicylate, imidazole salicylate, lysine acetylsalicylate, mesalamine, morpholine salicylate, 1 -naphthyl salicylate, olsalazine, parsalmide, phenyl acetylsalicylate, phenyl salicylate, salacetamide, salicylamide O-acetic acid, salicylsulfuric acid, salsalate or sulfasalazine; an aminoarylcarboxylic acid or a derivative thereof, e.g. enfenamic acid, etofenamate, flufenamic acid, isonixin, meclofenamic acid, mefenamic acid, niflumic acid, talniflumate, terofenamate or tolfenamic acid; an (aryl or heteroaryl)-alkylcarboxylic acid or a derivative thereof, such as acemetacin, alclofenac, amfenac, bufexamac, cinmetacin, clopirac, diclofenac, etodolac, felbinac, fenclofenac, fenclorac, fenclozic acid, fentiazac, glucametacin, ibufenac, indomethacin, isofezolac, isoxepac, lonazolac, metiazinic acid, oxametacine, pirazolac, proglumetacin, sulindac, tiaramide, tolmetin, zomepirac, bumadizon, butifen, fenbufen, xenbucin, clidanac, ketorolac, tinoridine, alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenoprofen, flunoxaprofen, flurbiprofen, ibuprofen, ibuproxam, indoprofen, ketoprofen, loxoprofen, miroprofen, naproxen, oxaprozin, piketoprofen, pirprofen, pranaprofen, protizinic acid, suprofen or tiaprofenic acid; a thiazinecarboxamide, e.g. droxicam, isoxicam, piroxicam or tenoxicam; a pyrazole derivative, e.g. difenamizole or epirizole; a pyrazolone derivative, e.g. apazone, benzpiperylon, febrazone, mofebutazone, morazone, oxyphenbutazone, phenylbutazone, pipebuzone, propyphenazone, ramifenazone, suxibuzone or thiazolinobutazone; or a non-steroidal antiinflammatory drug of another structure, e.g. epsilon-acetamidocaproic acid, S-adenosylmethionine, 3-amino-4-hydroxybutyric acid, amixetrine, bendazac, benzydamine, bucolome, difenpiramide, ditazol, emorfazone, guaiazulene, nabumetone, nimesulide, orgotein, oxaceprol, paranyline, perisoxal, pifoxime, proquazone, proxazole or tenidap; or a topically applicable salt thereof.

Particularly preferred NSAIDs are salicylic acid, etofenamate, flufenamic acid, niflumic acid, bufexamac, diclofenac, indomethacin, tolmetin, ibuprofen, ketoprofen, phenylbutazone, suxibuzone, piroxicam, guaiazulene, naproxen, felbinac and benzydamine and topically applicable salts thereof.

A topically applicable salt of a NSAID having an acidic group is e.g. an alkali metal or alkaline earth metal salt, e.g. the sodium, potassium, magnesium or calcium salt, an aluminium salt or a transition metal salt, e.g. the zinc or copper salt, or a corresponding salt with ammonia or organic amines. Organic amines that come into consideration are, for example, the following: alkylamines, such as mono-, di- or tri-lower alkylamines, e.g. ethylamine, tert-butylamine, diethylamine, diisopropylamine, trimethylamine or triethylamine, alkylenediamines, such as lower alkylenediamines, e.g. ethylenediamine, alkylamines substituted by phenyl, such as mono- or di-phenyl-lower alkylamines, e.g. benzylamine or 1- or 2-phenylethylamine, hydroxy-alkylamines, such as mono-, di- or tri-hydroxy-lower alkylamines, e.g. mono-, di- or tri-ethanolamine or diisopropanolamine, oligohydroxy-lower alkylamines, e.g. tris-(hydroxymethyl)-methylamine, hydroxy-lower alkyl-di-lower alkylamines, e.g. N,N-dimethylamino- or N,N-diethylamino-ethanol, amino sugars, such as those in which the amino group is optionally substituted by at least one lower alkyl group, e.g. D-glucosamine, D-galactosamine or marmosamine (derived from monosaccharides in which an alcoholic hydroxy group is replaced by an amino group) or N-methyl-D- glucosamine (an N-lower alkylated amino sugar), cycloalkylamines, such as mono- or di- cycloalkylamines, e.g. cyclohexylamine or dicyclohexylamine, basic amino acids, e.g. arginine, histidine, lysine or ornithine, or cyclic amines, such as lower alkyleneamines or lower alkenyleneamines, e.g. azirine, pyrrolidine, 1 -ethyl-pyrrolidine, 2-hydroxyethyl- pyrrolidine, piperidine, 1-ethyl-piperidine, 2-hydroxyethyl-piperidine or pyrroline, or lower alkyleneamines or lower alkenyleneamines in which the carbon chain is interrupted by aza (-NH-), N-lower alkylaza [-N(-lower alkyl)-], oxa (-O-) and/or thia (-S-), e.g. imidazoline, 3- methylimidazoline, piperazine, 4-methyl- or 4-ethylpiperazine, morpholine or thiomorpholine.

Menthyl lactate is a known compound available e.g. from Haarmann & Reimer GmbH (Germany) under the name FRESCOLAT, Type ML. The manufacturer's product literature indicates that it is a "cooling agent" and that it can be used in body care and cosmetic products in which "long lasting cooling and freshness are desired". Menthyl lactate is virtually odorless. The compound is recommended for use as a flavor in concentrations of 0.005% to 0.2% and in cosmetic and other external products in concentrations ranging from 0.2% to 2.0%. The maximum recommended amount of menthyl lactate as per the product literature is therefore 2.0% by weight. Nowhere is there any indication or suggestion that menthyl lactate should be used as an analgesic for relieving topical pain or at concentrations substantially in excess of those indicated by the product literature.

The structural formula of menthyl lactate is as follows:

As the compound contains 4 asymmetric carbon atoms, there are existing 16 different stereoisomers. The term "menthyl lactate" is intended to cover each of these stereoisomers as well as any racemates and any other mixtures of these stereoisomers. Preferred is the racemate of the following structure

which is derived from the naturally occuring (-)-menthol. This compound is available commercially as indicated above. It can also be readily made by processes known in the art by esterifiying the hydroxy group of menthol with lactic acid.

The combination according to the invention can be applied, usually in the form of a topical pharmaceutical composition, to any portion of the skin. However, application to the external genitalia, or the eyelids, or lips is not suggested, recommended, or usually desired.

The beneficial effects of the topical pharmaceutical compositions of the invention result from the combination of the known topical analgesic, antiinflammatory and antirheumatic properties of the NSAIDs with the so far unknown topical analgesic properties of menthyl lactate. In addition, the penetration of the NSAIDs through the skin is enhanced in an unexpected manner within the topical pharmaceutical compositions of the invention.

The beneficial effects, especially the topical antiinflammatory efficacy, of the topical pharmaceutical compositions of the invention can be demonstrated, for example, by the following tests.

Carrageenin induced paw edema in the rat, see e.g. C. Winter et al., Proc. Soc. Exp. Biol. Med. 1 11 (1962) 544-547.

Adjuvant arthritis in the rat, see e.g. C. Pearson et al., J. Exp. Med. 1 13 (1961 ) 485-509.

Randall and Selitto's test in the rat, see e.g. L. Randall and J. Selitto, Arch. Int. Pharmacodyn. 1 1 1 (1957) 409-419. The test mentioned as well as further tests are described in detail in: Y. Hiramatsu et al., "Assessment of topical non-steroidal anti-inflammatory drugs in animal models", Arzneimittelforschung 40 (1990) 1117-1124.

The safety of the compositions of the invention is confirmed by classical toxicological studies, such as the acute toxicity mice test, the acute rabbit skin/eye irritation test or sensitization tests. Adverse effects, such as rough skin or skin irritation, are not observed.

Preferably the invention relates to the topical use of a topically applicable NSAID selected from salicylic acid, etofenamate, flufenamic acid, niflumic acid, bufexamac, diclofenac, indomethacin, tolmetin, ibuprofen, ketoprofen, phenylbutazone, suxibuzone, piroxicam, guaiazulene, naproxen, felbinac and benzydamine, or a topically applicable salt thereof, in combination with menthyl lactate.

Especially the invention relates to the topical use of a topically applicable diclofenac salt in combination with menthyl lactate.

A topically applicable diclofenac salt is, for example, the sodium, potassium, ammonium, ethylammonium, diethylammonium, 2-hydroxyethylammonium or di-(2-hydroxyethyl)- ammonium salt, or the salt with 1 ,2-diaminoethane, benzylamine, pyrrolidine, 1 -ethyl- pyrrolidine, 2-hydroxyethyl-pyrrolidine, piperidine, 1 -ethyl-piperidine, 2-hydroxyethyl- piperidine or morpholine, and in particular the sodium, potassium or diethylammonium salt or the salt with 2-hydroxyethyl-pyrrolidine.

In particular, the invention relates to the use of a mixture of a non-steroidal antiinflammatory drug with menthyl lactate, in which mixture the non-steroidal antiinflammatory drug is present in an amount of from 0.1 up to 15 %, and menthyl lactate is present in an amount of from 1 .0 up to 15 %, especially of from 2.0 up to 15 %, very especially of from 2.5 up to 10 %, more especially of from 3 up to 8 %, and first and foremost of from 4 up to 8 %.

Normally, the combination of a NSAID and menthyl lactate is used in the form of a topical pharmaceutical composition which is also an object of the present invention. The invention therefore also relates to a topical pharmaceutical composition comprising at least one topically applicable non-steroidal antiinflammatory drug in combination with menthyl lactate together with at least one topically acceptable carrier material.

Preferably, the topically administered pharmaceutical compositions according to the invention comprise both the topically applicable non-steroidal antiinflammatory drug(s) and the menthyl lactate in pharmacologically effective amounts.

The daily dosage of the active ingredients depends on age and individual condition and on the mode of administration. For example, the topical pharmaceutical compositions, for example in the form of emulsion-gels, creams or ointments, may be applied once, twice or three times daily. But also more frequent daily applications are possible: such can provide a continual therapy which may lead to an even more rapid improvement of the painful conditions, inflammatory conditions or rheumatic diseases. Patches and bandages may be applied, for example, once daily or only once, twice or three times a week.

In a topical composition of the invention - as well in a mixture used according to the invention - the non-steroidal antiinflammatory drug(s) is (are) e.g. present in an amount of from 0.1 up to 15 %, especially of from 0.5 up to 5 %, and in particular of from 0.5 up to 2.5 %.

In a topical composition of the invention, menthyl lactate is preferably present in an amount of from 1.0 up to 15 %, especially of from 2.0 up to 15 %, very especially of from 2.5 up to 10 %, more especially of from 3 up to 8 %, and first and foremost of from 4 up to 8 %.

Pharmaceutical compositions suitable for topical administration are e.g. creams, lotions, ointments, microemulsions, fatty ointments, gels, emulsion-gels, pastes, foams, tinctures, solutions and transdermal therapeutic systems.

Creams or lotions are oil-in-water emulsions. As oily base there are used especially fatty alcohols, especially those containing from 12 to 18 carbon atoms, for example lauryl, cetyl or stearyl alcohol, fatty acids, especially those containing from 10 to 18 carbon atoms, for example palmitic or stearic acid, fatty acid esters, e.g. glyceryl tricaprilocaprate (neutral oil) or cetyl palmitate, liquid to solid waxes, for example isopropyl myristate, wool wax or beeswax, and/or hydrocarbons, especially liquid, semi-solid or solid substances or mixtures thereof, for example petroleum jelly (petrolatum) or paraffin oil. Suitable emulsifiers are surface-active substances having predominantly hydrophilic properties, such as corresponding non-ionic emulsifiers, for example fatty acid esters of polyalcohols and/or ethylene oxide adducts thereof, especially corresponding fatty acid esters with (poly)ethylene glycol, (poly)propylene glycol or sorbitol, the fatty acid moiety containing especially from 10 to 18 carbon atoms, especially partial glycerol fatty acid esters or partial fatty acid esters of polyhydroxyethylene sorbitan, such as polyglycerol fatty acid esters or polyoxyethylene sorbitan fatty acid esters (Tweens), and also polyoxyethylene fatty alcohol ethers or fatty acid esters, the fatty alcohol moiety containing especially from 12 to 18 carbon atoms and the fatty acid moiety especially from 10 to 18 carbon atoms, especially those having approximately from 2 to 24 ethylene glycol or ethylene oxide units, such as polyhydroxyethylenecetylstearyl ether (for example Cetomacrogol), polyhydroxyethylene- (7)-lauryl ether and polyhydroxyethyleneglycerol fatty acid ester, or corresponding ionic emulsifiers, such as alkali metal salts of fatty alcohol sulfates, especially having from 12 to 18 carbon atoms in the fatty alcohol moiety, for example sodium lauryl sulfate, sodium cetyl sulfate or sodium stearyl sulfate, which are usually used in the presence of fatty alcohols, for example cetyl alcohol or stearyl alcohol. Additives to the aqueous phase are, inter alia, agents that prevent the creams from drying out, for example humectants, such as polyalcohols, such as glycerol, sorbitol, propylene glycol and/or polyethylene glycols, and also preservatives, perfumes, gelling agents, etc..

Ointments are water-in-oil emulsions that contain up to 70 %, but preferably from approximately 20 % to approximately 50 %, water or aqueous phase. Suitable as fatty phase are especially hydrocarbons, for example petroleum jelly, paraffin oil and/or hard paraffins, which, in order to improve the water-binding capacity, preferably contain suitable hydroxy compounds, such as fatty alcohols or esters thereof, for example cetyl alcohol or wool wax alcohols, or wool wax or beeswax. Emulsifiers are corresponding lipophilic substances, for example of the type indicated above, such as sorbitan fatty acid esters (Spans), for example sorbitan oleate and/or sorbitan isostearate. Additives to the aqueous phase are, inter alia, humectants, such as polyalcohols, for example glycerol, propylene glycol, sorbitol and/or polyethylene glycol, and also preservatives, perfumes, etc. Microemulsions are isotropic systems based on the following four components water, a surfactant, for example a tensioactive, a lipid, such as a non-polar or polar oil, for example paraffin oil, and an alcohol or polyalcohol containing hpophilic groups, for example 2- octyldodecanol or ethoxalated glycerol or polyglycerol esters If desired, other additives may be added to the microemulsions

Fatty ointments are water-free and contain as base especially hydrocarbons, for example paraffin, petroleum jelly and/or liquid paraffins, also natural or partially synthetic fat, such as fatty acid esters of glycerol, for example coconut fatty acid tnglyceπde, or preferably hardened oils, for example hydrogenated groundnut oil, castor oil or waxes, also fatty acid partial esters of glycerol, for example glycerol mono- and di-stearate, and also, for example, the fatty alcohols increasing the water-absorption capacity, emulsifiers and/or additives mentioned in connection with the ointments

With gels, a distinction is made between aqueous gels, water-free gels and gels having a low water content, which gels consist of swellable, gel-forming materials There are used especially transparent hydrogels based on inorganic or organic macromolecules High molecular weight inorganic components having gel-forming properties are predominantly water-containing silicates, such as aluminium silicates, for example bentonite, magnesium aluminium silicates, for example Veegum, or colloidal silicic acid, for example Aerosil As high molecular weight organic substances there are used, for example, natural, semi- synthetic or synthetic macromolecules Natural and semi-synthetic polymers are derived, for example, from polysacchaπdes containing a great variety of carbohydrate components, such as celluloses, starches, tragacanth gum arable and agar-agar, and gelatin, alginic acid and salts thereof, for example sodium alginate, and deπvatives thereof, such as lower alkylcelluloses, for example methyl- or ethyl-cellulose, carboxy- or hydroxy-lower alkylcelluloses, for example carboxymethyl-or hydroxyethyl-cellulose The components of synthetic gel-forming macromolecules are, for example suitably substituted unsaturated aliphatic compounds such as vinyl alcohol, vinylpyrrolidme, acrylic or methacryhc acid Examples of such polymers are polyvinyl alcohol derivatives, such as polyviol, polyvmylpyrrolidines, such as collidone, polyacrylates and polymethacrylates, especially having a molecular weight of from approximately 80000 to approximately 1 million, or salts thereof, such as Rohagit S, Eudispert or Carbopol Customary additives, such as preservatives, humectants or perfumes, may be added to the gels Emulsion-gels - also called "emulgels" - represent topical compositions which combine the properties of a gel with those of an oil-m-water emulsion. In contrast to gels, they contain a lipid phase which due to its fat-restoring properties enables the formulation to be massaged in whilst, at the same time, the direct absorption into the skin is experienced as a pleasant property. Furthermore, one can observe an increased solubility for hpophilic active ingredients The advantages of emulsion-gels over oil-in-water emulsions reside in the enhanced cooling effect which is brought about by the coldness due to evaporation of the additional alkohol component Furthermore, one can observe an improved solubility of polar active ingredients

Emulsion-gels are normally characteπsed by having a pH of from 4 to 8, especially of from 5 to 7 5 They are, for example, composed as follows

(a) 0 1 to 10% of a non-steroidal antiinflammatory drug, especially one having at least one acidic group

(b) 0 1 to 15% of menthyl lactate

(c) 10 to 50% of a water-soluble, volatile lower alkanol having from 2 to 4 carbon atoms

(d) optionally 0 5 to 20% of a co-solvent

(e) 0.1 to 15%, especially 0.5 to 15% and in particular 3 to 15% of a lipid or of a mixture of different lipids

(f) 0 2 to 3% of a gel structure former

(g) optionally 0 5 to 5% of an emulsifier (h) non-essential components, and

(i) the remainder water (q s to make up to 100%)

The water-soluble, volatile lower alkanol having from 2 to 4 carbon atoms is e g ethanol or especially isopropanol, and also mixtures thereof

The co-solvent must be miscible with the aqueous-alcoholic phase Suitable for this purpose are, for example, polyhydnc alcohols, e g glycerine, ethylene glycol or propylene glycol, or, especially, poly-lower alkylene glycols, e g polyethylene glycol or polypropylene glycol

The lipids that can be used can be divided into those having non-emulsifying properties and those having self-emulsifying properties. The lipids can be of a vegetable or animal nature and also partly or completely synthetic. Accordingly, there come into consideration as fatty phase constituents, for example, lipids without ester linkages, such as hydrocarbons, fatty alcohols, sterols, fatty acids and salts thereof, and lipids having ester linkages, such as glycerides, waxes and phosphatides. Examples are: paraffins, capric alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol, lauric acid, stearic acid, olive oil, castor oil, bees wax, cetyl palmitate, lanolin, isopropyl myristate, isopropyl stearate, oleic acid decyl ester (CetiorV), ethyl oleate, caprylic/capric acid esters of saturated fatty alcohols (Cetiol'LC), egg or soya lecithin or polyhydroxyethylene cetyl stearyl ether (Cetomacrogor 1000).

As gel structure formers there are used inorganic and organic macromolecules. Inorganic macromolecules are e.g. water-containing silicates, such as aluminium silicate or magnesium aluminium silicates (VeegunrT), or colloidal silica (Aerosil⁸). As organic macromolecules there are used natural, semi-synthetic or synthetic macromolecules, for example celluloses, starches, tragacanth, agar-agar, alginic acid and salts thereof, lower alkyl celluloses, e.g. methyl, ethyl, carboxymethyl, hydroxyethyl, hydroxypropyl, hydroxypropylmethyl or ethylhydroxyethyl celluloses, gelatine, gum arabic, polyvinyl alcohols, polyvinyl pyrrolidones, polyacrylates and polymethacrylates (e.g. Carbopol¹").

As emulsifiers, preferably anion-active surfactants having an acidic hydrophilic group or non-ionogenic surfactants are used. Corresponding anionic emulsifiers are e.g. sodium palmitate, stearate, oleate and triethanolammonium stearate, sodium lauryl sulfate, sodium cetyl stearyl sulfate or sodium dioctyl sulfosuccinate. Non-ionic emulsifiers are, for example, fatty acid esters with e.g. lower alkanols, ethylene glycol, propylene glycol, sorbitol, polyethylene glycol or polypropylene glycol; or polyethylene and polypropylene glycol ethers, e.g. polyhydroxyethylene cetyl stearyl ether (Cetomacrogor 1000).

As non-essential components there come into consideration, for example, chemical stabilizers (including antioxidants), moisture-retaining agents, optionally bases for neutralizing acidic groups and/or perfumes.

Foams are administered, for example, from pressurised containers and are liquid oil-in- water emulsions in aerosol form; unsubstituted hydrocarbons, such as alkanes, for example propane and/or butane, are used as propellant. As oil phase there are used, inter aHa, hydrocarbons, for example paraffin oil, fatty alcohols, for example cetyl alcohol, fatty acid esters, for example isopropyl myristate, and/or other waxes. As emulsifiers there are used, inter alia, mixtures of emulsifiers having predominantly hydrophilic properties, such as polyoxyethylene sorbitan fatty acid esters (Tweens), and emulsifiers having predominantly lipophilic properties, such as sorbitan fatty acid esters (Spans). The customary additives, such as preservatives, etc., are also added.

Tinctures and solutions generally have an ethanolic base, to which water may be added and to which there are added, inter alia, polyalcohols, for example glycerol, glycols and/or polyethylene glycol, as humectants for reducing evaporation, and fat-restoring substances, such as fatty acid esters with low molecular weight polyethylene glycols, propylene glycol or glycerol, that is to say lipophilic substances that are soluble in the aqueous mixture, as a replacement for the fatty substances removed from the skin by the ethanol, and, if necessary, other adjuncts and additives. Suitable tinctures or solutions may also be applied in spray form by means of suitable devices.

Transdermal therapeutic systems with - in particular - local delivery of the active substances contain an effective amount of each of the active ingredients optionally together with a carrier. Useful carriers comprise absorbable pharmacological suitable solvents to assist passage of the active ingredients through the skin. Transdermal delivery systems are, for example, in the form of a patch comprising (a) a substrate ( = backing layer or film), (b) a matrix containing the active ingredients, optionally carriers and optionally (but preferably) a special adhesive for attaching the system to the skin, and normally (c) a protection foil ( = release liner). The matrix (b) is normally present as a mixture of all components or may consist of separate layers.

The manufacture of the topically administrable pharmaceutical preparations is effected in a manner known per se. for example by dissolving or suspending the active ingredients in the base or, if necessary, in a portion thereof. When the active ingredients are administered in the form of a solution, they are generally dissolved in one of the two phases before emulsification. The following examples are intended to illustrate the invention.

Example 1 : An emulsion-gel containing the diethylammonium salt of diclofenac and menthyl lactate is manufactured as follows.

Composition

(a) diethylammonium salt of diclofenac 1.16 % by weight

(b) menthyl lactate 6.0 % by weight

(c) isopropanol 20.0 % by weight

(d) polyethylene glycol 300 3.0 % by weight

(e) polyhydroxyethylene cetyl stearyl ether (CETOMACROGOL 1000) 2.0 % by weight

(f) paraffin oil, viscous 2.5 % by weight

(g) caprylic/capric acid ester (CETIOL LC) 2.5 % by weight (h) acrylic acid polymerisate (CARBOPOL 934 P) 1.0 % by weight (i) diethylamine 0.7 % by weight (j) sodium sulphite 0.1 % by weight (k) water, demineralised to make up to 100 % by weight

The acrylic acid polymerisate is dispersed in a portion of water by means of a rotor-stator homogeniser (for example HOMOREX). A solution of the diethylammonium salt of diclofenac, diethylamine, sodium sulphite and polyethylene glycol 300 in isopropanol and the remaining water is added thereto and distributed homogeneously. To form the fatty phase, the polyhydroxyethylene cetyl stearyl ether, caprylic/capric acid ester and the paraffin oil are melted together at 75°. Menthyl lactate is added to the fatty phase, and then the whole fatty phase is slowly added to the previously formed gel and emulsified.

Example 2: An emulsion-gel containing the sodium salt of diclofenac and menthyl lactate is manufactured as follows.

Composition

(a) diclofenac sodium 1.0 % by weight (b) menthyl lactate 6.0 % by weight

(c) propylene glycol 20.0 % by weight

(d) polyethylene glycol 300 3.0 % by weight

(e) polyhydroxyethylene cetyl stearyl ether (CETOMACROGOL 1000) 2.0 % by weight

(f) paraffin oil, viscous 2.5 % by weight

(g) caprylic/capric acid ester (CETIOL LC) 2.5 % by weight

(h) acrylic acid polymerisate (CARBOPOL 934 P) 1.0 % by weight

(i) diethylamine 0.7 % by weight

(j) sodium sulphite 0.1 % by weight

(k) water, demineralised to make up to 100 % by weight

The acrylic acid polymerisate is dispersed in a portion of water by means of a rotor-stator homogeniser (for example HOMOREX). A solution of diclofenac sodium, menthyl lactate, diethylamine, sodium sulphite and polyethylene glycol 300 in propylene glycol and the remaining water is added thereto and distributed homogeneously. To form the fatty phase, the polyhydroxyethylene cetyl stearyl ether, caprylic/capric acid ester and the paraffin oil are melted together at 75°, slowly added to the previously formed gel and emulsified.

Claims

Patent claims

1. Use of at least one topically applicable non-steroidal antiinflammatory drug in combination with menthyl lactate for the manufacture of a topical medicament for the treatment of painful conditions, inflammatory conditions or rheumatic diseases.

2. Use according to claim 1 , where the topically applicable non-steroidal antiinflammatory drug(s) is (are) selected from salicylic acid, etofenamate, flufenamic acid, niflumic acid, bufexamac, diclofenac, indomethacin, tolmetin, ibuprofen, ketoprofen, phenylbutazone, suxibuzone, piroxicam, guaiazulene, naproxen, felbinac, benzydamine and topically applicable salts thereof.

3. Use according to claim 1 , where the topically applicable non-steroidal antiinflammatory drug is a topically applicable diclofenac salt.

4. Use according to claim 1 , where the topically applicable non-steroidal antiinflammatory drug is a topically applicable diclofenac salt selected from the sodium, potassium, diethylammonium salt or the salt with 2-hydroxyethyl-pyrrolidine.

5. Use of at least one topically applicable non-steroidal antiinflammatory drug in combination with menthyl lactate according to claim 1 , where the topically applicable non¬ steroidal antiinflammatory drug(s) is (are) present in an amount of from 0.1 up to 15 % and menthyl lactate is present in an amount of from 2.0 up to 15 % in the topical medicament manufactured.

6. Use of at least one topically applicable non-steroidal antiinflammatory drug in combination with menthyl lactate according to claim 1 , where the topically applicable non¬ steroidal antiinflammatory drug(s) is (are) present in an amount of from 0.1 up to 15 % and menthyl lactate is present in an amount of from 2.5 up to 15 % in the topical medicament manufactured.

7. A topical pharmaceutical composition comprising at least one topically applicable non^¬ steroidal antiinflammatory drug in combination with menthyl lactate together with at least one topically acceptable carrier material.

8. A topical pharmaceutical composition according to claim 7, wherein the topically applicable non-steroidal antiinflammatory drug(s) is (are) selected from salicylic acid, etofenamate, flufenamic acid, niflumic acid, bufexamac, diclofenac, indomethacin, tolmetin, ibuprofen, ketoprofen, phenylbutazone, suxibuzone, piroxicam, guaiazulene, naproxen, felbinac, benzydamine and topically applicable salts thereof.

9. A topical pharmaceutical composition according to claim 7, wherein the topically applicable non-steroidal antiinflammatory drug is a topically applicable diclofenac salt.

10. A topical pharmaceutical composition according to claim 7, wherein the topically applicable non-steroidal antiinflammatory drug is a topically applicable diclofenac salt selected from the sodium, potassium, diethylammonium salt or the salt with 2-hydroxyethyl- pyrrolidine.

1 1. A topical pharmaceutical composition according to any one of claims 7 to 10, wherein the topically applicable non-steroidal antiinflammatory drug(s) is (are) present in an amount of from 0.1 up to 15 %, and menthyl lactate is present in an amount of from 2.0 up to 15 %.

12. A topical pharmaceutical composition according to any one of claims 7 to 10, wherein the topically applicable non-steroidal antiinflammatory drug(s) is (are) present in an amount of from 0.1 up to 15 %, and menthyl lactate is present in an amount of from 2.5 up to 15 %.

13. A topical pharmaceutical composition according to any one of claims 7 to 12, which is in the form of an emulsion-gel, a gel, a cream, a lotion, an ointment, a patch or a bandage.